Administration of non-oral androgenic steroids to women

ABSTRACT

The present invention provides compositions, methods, and kits for improving health in a woman having elevated SHBG levels, or who is receiving oral estrogen supplementation, by non-orally administering an effective amount of an androgenic steroid. Further, the present invention provides compositions, methods, and kits for coadministering an effective amount of an orally administered estrogen and an effective amount of a non-orally administered androgenic steroid for women in need of estrogen supplementation.

RELATED APPLICATIONS

[0001] This application claims priority to United States ProvisionalPatent Applications Serial No. 60/138,851; Serial No. 60/138,854, andSerial No.:60/139,323, each of which was filed on Jun. 11, 1999. Each ofthese applications is hereby incorporated by reference.

THE FIELD OF THE INVENTION

[0002] This invention broadly relates to the administration of androgensto women. Accordingly, this invention covers the fields ofpharmaceutical sciences and medicine.

BACKGROUND OF THE INVENTION

[0003] It is known that a functional level of androgenic hormones infemales promotes sexual health and activity, feelings of well being,maximizes muscle mass and function, and inhibits bone loss. Further, afunctional level of androgenic hormones may promote cardiovascular andcoronary health, decrease breast tenderness, decrease vasomotorinstability, modulate immune function, enhance certain cognitiveabilities, improve urogential health, reduce estrogen supplementationrelated side effects, and provide direct neuroprotective effects.

[0004] The attainment of functional levels of androgenic hormones inwomen, such as testosterone, may be influenced by the serumconcentrations of sex hormone binding globulin (SHBG). SHBG is a proteinproduced by the liver that binds sex hormones such as testosterone andestradiol in the blood. The SHBG-bound sex hormones are generally“non-functional”, i.e., unavailable to exert biological action at sexhormone receptors in target tissues and/or undergo clearance from theblood.

[0005] Use of oral estrogens raises serum levels of SHBG. SHBG levelsare also elevated in various conditions, e.g., hyperthyroidism andpregnancy, and by certain other medications, e.g., anti-convulsants.Elevated SHBG levels alter the levels of androgenic hormones and thedoses needed to achieve functional levels.

[0006] The present invention provides methods, compositions, and kits toachieve functional levels of androgenic steroids in women with elevatedSHBG levels and thus improve their health.

SUMMARY OF THE INVENTION

[0007] Accordingly, the present invention provides a method and kit forimproving health in a woman who has an elevated or substantiallyelevated level of sex hormone binding globulin (SHBG). Additionally, thepresent invention provides a method and kit for improving health in awoman receiving oral estrogen supplementation. Further, the presentinvention provides a method and kit for improving health in a woman inneed of oral estrogen supplementation.

[0008] In one aspect, such methods include non-orally administering anandrogenic steroid, in an amount sufficient to provide a therapeuticeffect in the presence of elevated, or substantially elevated SHBGlevels. In another aspect, such methods include non-orally administeringan androgenic steroid, in an amount sufficient to provide a therapeuticeffect in the presence of an oral estrogen administration. In yetanother aspect, such methods include co-administering an effectiveamount of an orally administered estrogen and an amount of a non-orallyadministered androgenic steroid which is sufficient to provide atherapeutic effect in the presence of oral estrogen administration.

[0009] Examples of specific androgenic steroids which may be utilizedinclude but are not limited to: testosterone, methyltestosterone,androstenedione, adrenosterone, dehydroepiandrosterone, oxymetholone,fluoxymesterone, methandrostenolone, testolactone, pregnenolone,17α-methylnortestosterone, norethandrolone, dihydrotestosterone,danazol, oxymetholone, androsterone, nandrolone, stanozolol,ethylestrenol, oxandrolone, bolasterone and mesterolone, testosteronepropionate, testosterone cypionate, testosterone phenylacetate, andtestosterone enanthate, testosterone acetate, testosterone buciclate,testosterone heptanoate, testosterone decanoate, testosterone caprate,testosterone isocaprate, isomers and derivatives thereof, and acombination thereof.

[0010] The amount of androgenic steroid to be administered may bemeasured according to several different parameters. In one aspect, theamount of androgenic steroid administered may be an amount sufficient toachieve a therapeutic effect equivalent to a total testosterone serumlevel of from about 15 to about 1000 ng/dl. In another aspect of thepresent invention, the amount of androgenic steroid administered may bean amount sufficient to achieve a therapeutic effect equivalent to afree testosterone serum level of from about 0.5 to about 30 pg/ml. In afurther aspect of the present invention, the amount of androgenicsteroid administered may be an amount sufficient to achieve atherapeutic effect equivalent to a bioavailable testosterone serum levelof from about 1 to about 70 ng/dl. In yet another aspect of the presentinvention, the amount of androgenic steroid administered may be anamount sufficient to achieve a therapeutic effect equivalent to atestosterone dosage of at least about 50 mcg/day.

[0011] Examples of specific estrogens which may be utilized inconnection with the method of the present invention include but are notlimited to: 17β-estradiol, 17α-estradiol, conjugated equine estrogen,esterified estrogen, micronized estradiol, sodium estrogen sulfate,ethinyl estradiol, estrone, tibolone, selective estrogen receptormodulators (SERM's), phytoestrogens, isomers and derivatives thereof,and a combination thereof. In one aspect of the invention, the amount ofestrogen administered may be a dosage sufficient to achieve atherapeutic effect equivalent to a conjugated equine estrogen dosage ofabout 0.2 to about 3.0 mg/day.

[0012] Various forms of non-oral administration of androgen may beemployed in accordance with the methods of the present invention,including but not limited to: topical administration, or parenteraladministration, or a combination thereof. In one aspect, the forms oftopical administration include without limitation, transdermal, ortransmucosal, or sublingual, or a combination thereof. In anotheraspect, the parentarel forms of administration include withoutlimitation, intramuscular injection, or subcutaneous implantation, or acombination thereof.

[0013] A progestin may be coadministered with the androgenic steroid andthe estrogen, when desired. In one aspect, the progestin administrationmay be an amount sufficient to provide endometrial safety during oralestrogen administration. In another aspect, the progestin administrationmay be an amount sufficient to provide effective contraception.

[0014] There are many indicators of the improved health which may occuras a result of the method of the present invention. Of particular note,without limitation thereto, are the restoration, enhancement,improvement, or prevention of characteristics such as: sexual desire,frequency of sexual activity, stimulation to sexual organs, ability toachieve orgasm, pleasure in sexual activity, vital energy, sense ofwell-being, mood and sense of emotional well being, shyness, cognitiveabilities, muscle mass and function, body composition, bone mineraldensity, skin and hair condition, pubic hair, urogenital atrophy,vaginal dryness, dry eyes, health in autoimmune conditions, vasomotorinstability, breast tenderness, symptoms of premenstrual syndrome, and acombination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]FIG. 1 shows the change in total testosterone level versusbaseline SHBG level during application of transdermal testosterone patch(300 mcg/day nominal delivery) to patients concomitantly receivingtransdermal estradiol or oral conjugated equine estrogens.

[0016]FIG. 2 shows the change in free testosterone level versus baselineSHBG level during application of transdermal testosterone patch (300mcg/day nominal delivery) to patients concomitantly receivingtransdermal estradiol or oral conjugated equine estrogens.

DETAILED DESCRIPTION

[0017] A. Definitions

[0018] In describing and claiming the present invention, the followingterminology will be used.

[0019] The singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a transdermal patch” includes reference to one or more ofsuch transdermal patches, and reference to “an estrogen” includesreference to one or more of such estrogens.

[0020] “Sex hormone” refers to any hormone which affects the growth orfunction of the reproductive organs, or the development of secondary sexcharacteristics. In one aspect, sex hormones include, but are notlimited to androgens, estrogens, progestins, and other hormones whichare known in the art.

[0021] “Androgenic steroid,” or “androgen,” refer to a steroid, naturalor synthetic, which exerts its biological or pharmacological actionprimarily by binding to androgen receptors. Examples include, but arenot limited to: testosterone, methyltestosterone, androstenedione,adrenosterone, dehydroepiandrosterone, oxymetholone, fluoxymesterone,methandrostenolone, testolactone, pregnenolone,17α-methylnortestosterone, norethandrolone, dihydrotestosterone,danazol, androsterone, nandrolone, stanozolol, ethylestrenol,oxandrolone, bolasterone, mesterolone, testosterone propionate,testosterone cypionate, testosterone phenylacetate, and testosteroneenanthate, testosterone acetate, testosterone buciclate, testosteroneheptanoate, testosterone decanoate, testosterone caprate, testosteroneisocaprate, as well as esters, derivatives, prodrugs, and isomersthereof.

[0022] “Testosterone” refers to the compound having the IUPAC names(17β)-17-Hydroxyandrost-4-en-3-one, and Δ⁴-androsten-17β-ol-3-one, aswell as their isomers. Testosterone is listed in the Merck Index, entryno. 9322, at page 1569, 12th ed., (1996).

[0023] “Estrogen”, and “estrogenic hormone” refer to any substance,natural or synthetic, that exerts a biological or pharmacological actionprimarily by binding to estrogen receptors. Examples include but are notlimited to: 17-β-estradiol, 17-α-estradiol, estriol, estrone, andphytoestrogens. These estrogens may be derivatized or modified to form,for example, conjugated equine estrogens, esterified estrogens, ethinylestradiol, etc. Examples of esterified estrogens include but are notlimited to: estradiol-3,17-diacetate, estradiol-3-acetate,estradiol-17-acetate, estradiol-3,17-divalerate, estradiol-3-valerate,estradiol-17-valerate. Also included are selective estrogen receptormodulators (SERMS), for example raloxifene, available under thetradename Evista® from Eli Lilly, and the like. The estrogens may alsobe present as salts, (e.g., as sodium estrogen sulfate), isomers, orprodrugs.

[0024] Also included, are phytoestrogens which are plant-derivedestrogens. Isoflavones are one major form of phytoestrogen and have acommon diphenolic structure that resembles the structure of potentsynthetic estrogens such as diethylstilbesterol and hexestrol. Majorisoflavones found in humans include, but are not limited to genistein,diadzein, and equol.

[0025] “Oral estrogens” refers to any estrogen which is in a dosage formsuitable for oral administration. Conjugated equine estrogens,esterified estrogens and micronized estradiol are examples of oralestrogens. Commercially available oral estrogen products includeconjugated equine estrogens available under the trade name Premarin®from Wyeth-Ayerst Laboratories, esterified estrogens available under thetrade name Estratab® from Solvay Pharmaceuticals, and micronized 17-βestradiol available under the trade name Estrace® from Bristol MeyersSquibb.

[0026] “Progestin,” or “progestogen” refer to any substance, natural orsynthetic, that exerts a biological or pharmacological action primarilyby binding to progestin receptors. Examples include, but are not limitedto: progesterone, medroxy-progesterone acetate, norethindrone, andnorethindrone acetate, esters, derivatives, prodrugs, and isomersthereof. Progestin has been administered to women in order to achieve avariety of effects. Examples without limitation include providingendometrial safety during concomitant estrogen administration, andproviding effective contraception. While the amount of progestinrequired to achieve such effects may vary from woman to woman, methodsfor determining appropriate or effective amounts of progestin in orderto achieve a designed purpose or effect, are well known to those ofordinary skill in the art.

[0027] “Sex hormone binding globulin”, or “SHBG”, also known as sexhormone binding protein (SHBP) and testosterone estradiol bindingglobulin (TeBG), refers to a serum protein that binds a variety of sexhormones with high affinity (See Table 1; from Dunn et al., Transport ofSteroid Hormones: Binding of 21 Endogenous Steroids to BothTestosterone-Binding Globulin and Corticosteroid-Binding Globulin inHuman Plasma, J. Clinical Endocrinology and Metabolism, Vol. 53:58-67(1981)). Represented binding affinity constants (K values) forparticular sex hormones and SHBG are provided in Table 1 as follows.(adapted from Dunn et al. 1981) TABLE 1 Sex Hormone K (10⁶ Liter/mole)androstanediol 1300 androstenediol 1500 androstenedione 29 androsterone14 dehydroepiandrosterone 66 dihydrotestosterone 5500 estradiol 680estriol 4.3 estrone 150 progesterone 8.8 17-hydroxyprogesterone 9.9testosterone 1600

[0028] For the purposes of this application, SHBG binding affinityconstants exceeding about 1×10⁶ Liter/mole indicate high affinitybinding.

[0029] The structure and proposed functions of SHBG have been describedand characterized. See, for example, Rosner et al., Sex Hormone-BindingGlobulin Mediates Steroid Hormone Signal Transduction at the PlasmaMembrane, J. Steroid Biochem. Mol. Biol. Vol. 69:481-5 (1999); Petra, P.H. The plasma Sex Steroid Binding Protein (SBP or SHBG). A CriticalReview of Recent Developments on the Structure, Molecular Biology, andFunction, J. Steroid Biochem. Mol. Biol., Vol. 40:735-53 (1991). Avariety of methods have been used to quantify the serum concentrationsof SHBG, including ammonium sulfate precipitation, gel filtration,equilibrium dialysis, dextran-coated charcoal, and radioimmunoassay.See, for example, Khan et al., Radioimmunoassay for HumanTestosterone-Estradiol-Binding Globulin, J. Clinical Endocrinology andMetabolism, Vol. 54:705-710 (1982). Using a validated monoclonalimmunoradiometric assay (Endocrine Sciences, Calabassas Hills, Calif.),the mean serum SHBG level in healthy premenopausal women was found to be84 nmole/Liter and the normal range 36 to 185 nmole/Liter. Serum SHBGlevels are known to be elevated in women treated with oral estrogens,estrogen-containing oral contraceptives, clomiphene, tamoxifen,raloxifene, phenytoin, and sodium valproate, as well as in women who arepregnant, hyperthyroid, have chronic liver disease and HIV-infection.See for example, Bond et al., Sex Hormone Binding Globulin in ClinicalPerspective, Acta. Obstet. Gynecol. Scand., Vol. 66:255-262 (1987);Miller et al. Transdermal Testosterone Administration in Women withAcquired Immunodeficiency Syndrome Wasting: A Pilot Study, J. ofClinical Endocrinology and Metabolism, Vol. 83: 27172725 (1998).

[0030] “Administration,” and “administering” refer to the manner inwhich a drug is presented to a subject. Administration can beaccomplished by various routes well-known in the art such as oral, andnon-oral methods.

[0031] “Oral administration” can be achieved by swallowing, chewing, orsucking of an oral dosage form comprising the drug. “Non-oraladministration” represents any method of administration in which a drugcomposition is not provided in a solid or liquid oral dosage form,wherein such solid or liquid oral dosage form is traditionally intendedto substantially release and/or deliver the drug in the gastrointestinaltract beyond the mouth and/or buccal cavity. Such solid dosage formsinclude conventional tablets, capsules, caplets, etc., which do notsubstantially release the drug in the mouth or in the oral cavity.

[0032] It is appreciated that many oral liquid dosage forms such assolutions, suspensions, emulsions, etc., and some oral solid dosageforms may release some of the drug in the mouth or in the oral cavityduring the swallowing of these formulations. However, due to their veryshort transit time through the mouth, or oral cavity, the release ofdrug from these formulations in the mouth, or oral cavity, is consideredde minimus or insubstantial. Thus, buccal patches, adhesive films,sublingual tablets, and lozenges that are designed to release the drugin the mouth are non-oral compositions for the present purposes.

[0033] Thus, the term “non-oral” includes parenteral, topical,inhalation, implant, occular, nasal, and vaginal or rectal formulationsand administrations. Further, implant formulations are to be included inthe term “non-oral,” regardless of the physical location ofimplantation.

[0034] “Parenteral” administration can be achieved by injecting a drugcomposition intravenously, intra-arterially, intramuscularly,intrathecally, or subcutaneously, etc.

[0035] “Topical formulation” means a composition in which the drug maybe placed for direct application to a skin surface and from which aneffective amount of drug is released. Examples of topical formulationsinclude but are not limited to ointments, creams, gels, transdermalpatches, sprays, vaginal rings, and pastes. “Transdermal” refers to theroute of administration that facilitates transfer of a drug through askin surface wherein a transdermal composition is administered to theskin surface.

[0036] Transdermal administration can be accomplished by applying,pasting, rolling, attaching, pouring, pressing, rubbing, etc., of atransdermal preparation onto a skin surface. These and additionalmethods of administration are well-known in the art.

[0037] “Transdermal delivery system,” “transdermal patches” or simply“patches” refer to a matrix or liquid reservoir type of delivery devicewhich is used to transdermally deliver defined doses of a substance,over a specific application period.

[0038] One example of a transdermal patch for administering anandrogenic steroid in accordance with this invention is a matrix-typepatch which comprises an occlusive backing that is impermeable to theandrogen steroids and defines the face or top surface of the patch and asolid or semisolid matrix layer comprised of a homogeneous blend of thehormone, a polymeric pressure sensitive adhesive carrier, and optionallyone or more skin permeation enhancers. Matrix patches are known in theart of transdermal drug delivery. Examples without limitation, ofadhesive matrix transdermal patches are those described or referred toin U.S. Pat. Nos. 5,122,383 and 5,460,820 which are incorporated byreference in their entirety.

[0039] Another example of a transdermal patch for administering anandrogenic steroid in accordance with this invention is a liquidreservoir system (LRS) type patch which comprises androgen, and otheroptional ingredients, such as a permeation enhancer, in a carriervehicle. The carrier vehicle comprises a fluid of desired viscosity,such as a gel or ointment, which is formulated for confinement in areservoir having an impermeable backing and a skin contacting permeablemembrane, or membrane adhesive laminate providing diffusional contactbetween the reservoir contents and the skin. For application, a peelablerelease liner is removed and the patch is attached to the skin surface.LRS patches are known in the art of transdermal drug delivery. Exampleswithout limitation, of LRS transdermal patches are those described orreferred to in U.S. Pat. Nos. 4,849,224, 4,983,395, which areincorporated by reference in their entirety.

[0040] “Skin,” “skin surface,” “derma,” “epidermis,” and similar termsare used interchangeably herein, and refer to not only the outer skin ofa subject comprising the epidermis, but also to mucosal surfaces towhich a drug composition may be administered. Examples of mucosalsurfaces include the mucosal of the respiratory (including nasal andpulmonary), oral (mouth and buccal), vaginal, introital, labial, andrectal surfaces. Hence the terms “transdermal” encompasses“transmucosal” as well.

[0041] “Coadministration” and similar terms refer to administration ofmultiple substances to one individual, either simultaneously orsequentially. Thus, with reference to estrogen and androgen, the termincludes any situation in which women are receiving oral estrogen andnon-oral androgen. The term does not imply that the estrogen andandrogen have to be administered at the same time. Rather, as long as awoman is receiving oral estrogen, administration of non-oral androgenwill be within the present definition for “coadministration”. It shouldbe understood that the estrogen and the androgen need not be provided ina single product or by an identical route to be “coadministered”.

[0042] The terms “formulation” and “composition” are usedinterchangeably herein. The terms “pharmaceutical” and “drug” are alsoused interchangeably to refer to a pharmacologically active substance orcomposition. These terms of art are well-known in the pharmaceutical andmedicinal arts.

[0043] “Total serum level”, “total blood level”, and “endogenous serumlevel,” refer to the total serum levels of androgen or estrogen,including all protein-bound and free androgen or estrogen. Certainproteins such as albumin bind androgen or estrogen with a low affinitysuch that these sex hormones are functional (bioavailable) (i.e.,produce their known or intended biological effect). By contrast, someproteins such as SHBG bind androgen or estrogen with high affinity torender them non-functional. One of skill in the art knows how to measureand characterize these types of bindings. See, for example Dunn et al.

[0044] Thus, the term “total testosterone serum level” refers to the sumof: (1) free testosterone; (2) testosterone which is weakly bound toserum proteins, such as albumin-bound testosterone; and (3) testosteronewhich is tightly bound bound to high affinity binding serum proteins,such as SHBG-bound testosterone.

[0045] The term “protein-bound” includes all types of protein bindings.

[0046] Total serum testosterone can be measured by known assaytechniques such as a radioimmunoassay (RIA). See for example the RIAprocedure used by Endocrine Sciences, Inc. (Calabassas Hills, Calif.).This procedure is based on the published RIA by Furuyama et al.,Radioimmunoassay for Plasma Testosterone, Steroids. 1970;16:415-428.With this assay method, the normal range of total serum testosteronelevels measured in healthy premenopausal women by Endocrine Sciences,Inc. was reported to be 14 to 54.3 ng/dL (Miller et al. 1998).

[0047] “Endogenous free testosterone level” or “physiological freetestosterone level,” shall refer to the free testosterone (FT) serumlevel that is normally found in adult women without symptoms associatedwith testosterone deficiency and/or testosterone excess, and/orimbalanced estrogen/androgen symptoms.

[0048] “Bioavailable”, “serum bioavailable”, and similar terms refer toandrogen or estrogen that is not bound to SHBG. Therefore androgen whichis “free” (unbound) or “weakly bound to” (easily dissociates from) serumalbumin is considered to be bioavailable to tissues. Because of the highbinding capacity (non-saturability) of albumin for testosterone, theserum concentration of albumin-bound testosterone will, in general, beproportional to the concentration of free testosterone. Theproportionality factor corresponds to the product of thealbumin-testosterone binding constant (3.6×10⁴ L/mole) and the serumalbumin concentration (expressed in mole/Liter). See, Vermeulen et al.,A Critical Evaluation of Simple Methods for the Estimation of FreeTestosterone in Serum, J. of Clinical Endocrinology and Metabolism Vol.84:3666-3672 (1999). Since the concentration of serum albumin ismaintained within a relatively narrow range (e.g. 4-5 g/dL;5.8×10^(−4−7.6×10) ⁻⁴ mole/Liter), this proportionality factor isapproximately 22. As a consequence of this relationship theconcentration of bioavailable testosterone may be approximately 23 timesthe concentration of free testosterone, independent of theconcentrations of total testosterone and SHBG.

[0049] The concentration of bioavailable testosterone is commonlymeasured using an ammonium sulfate precipitation method. See, forexample, Nankin et al. Daytime Titers of Testosterone, LH, Estrone,Estradiol, and Testosterone-Binding Protein: Acute Effects of LH andLH-Releasing Hormone in Men, J. Clinical Endocrinology Metabolism, Vol.41:271-81 (1975). Using this method the normal range of bioavailabletestosterone levels measured in healthy premenopausal women by EndocrineSciences, Inc. was reported to be 1.6 to 12.7 ng/dL, or about 2 to 13ng/dL.

[0050] “Free,” “unbound,” or similar terms, refers to the androgen orestrogen which is unattached to any protein, such as SHBG, or albumin.Therefore, androgen or estrogen which is not protein bound is considered“free”.

[0051] By way of example without limitation, terms such as “freetestosterone,” “unbound testosterone,” “serum free testosterone,” referto the testosterone in the serum that is not protein bound. Serum freetestosterone levels can measured by a variety of laboratory methods,including equilibrium dialysis, ultrafiltration, an analogue RIA method,and by calculation from the levels of total testosterone, SHBG andalbumin. See, for example, Winters et al. The Analog Free TestosteroneAssay: Are the Results in Men Clinically Useful?, Clinical ChemistryVol. 44:2178-2182 (1998); see also, Vermeulen et al. (1999). Theequilibrium dialysis method, is currently believed to provide the mostaccurate results. See, Mathor et al., Free Plasma Testosterone LevelsDuring the Normal Menstrual Cycle, J. Endocrinol Invest Vol. 8:437-41(1985). Using this method the normal range of free testosterone levelsmeasured in healthy premenopausal women by Endocrine Sciences, Inc. wasreported to be 1.3 to 6.8 pg/mL, or about 2 to 7 pg/mL.

[0052] “Woman” refers to a human female who benefits from an androgen orestrogen supplementation in any way. In one aspect, the female may bemenopausal due to age, oophorectomy, or ovarian failure. In anotheraspect, the female may be receiving oral estrogens for beneficialeffects such as to prevent or retard bone loss, to prevent or retardchanges in blood lipids which might otherwise predispose the woman tocardiovascular disease. In yet another aspect, the female may display adeficiency, or imbalance of estrogen and androgenic hormones. In yetanother aspect, the female may be receiving oral estrogens forcontraception.

[0053] “Improving health” refers to reducing, improving, or preventingthe incidence and/or intensity of symptoms associated with androgenicsteroid deficiency. Examples of such symptoms include but are notlimited to: sexual dysfunction, which can manifest in loss of sexualdesire, decreased sensitivity to sexual stimulation, decreasedarousability and capacity for orgasm, diminished vital energy, depressedmood, diminished sense of well-being, increased shyness, loss of musclemass and function, unfavorable body composition, i.e., lean to fat massratio, thinning and loss of pubic hair, urogenital atrophy, dry andbrittle scalp hair, dry skin, decreased cognitive abilities, dry eyes,autoimmune phenomena, and a combination thereof.

[0054] Increases and decreases in the presence and severity of suchsymptoms may be ascertained through various devices known in the art forevaluating each particular symptom. For example, sexual function inwomen may be evaluated using self-assessment questionnaires, such as theBrief Index of Sexual Functioning for Women, (Taylor et al 1994);Derogatis Interview for Sexual Functioning, Derogatis, L., The Derogatisinterview for Sexual Functioning (DISF/DISF-SR): an introductory report,J. Sex. Marital Ther. Winter 23(4):291-304 (1997); and otherquestionnaires, such as Derogatis et al., Psychological assessmentmeasures of human sexual functioning in clinical Trials, Int. J. Impot.Res., May 10 Suppl. 2:S13-20 (1998); as well as by genital blood flowmethods (Laan 1998). Muscle mass, body composition and bone mineraldensity are commonly measured using dual energy x-ray absorptiometry(DEXA). Mood, well-being and neurocognitive function can be measured bythe Beck Depression Inventory (Beck et al 1961), the PsychologicalGeneral Well-being Index (Dupuy 1984), and a battery of neurocognitivefunction tests. Dry eye syndrome can be assessed by tear function tests,e.g., osmolality, volume, flow rate, Shirmer's test, by use ofartificial tear preparations, and by subjective questionnaires. See, forexample, Mathers et al. Menopause and Tear Function: The Influence ofProlactin and Sex Hormones on Human Tear Production, Cornea Vol.17:353-8 (1998). Immune function can be assessed by the titres ofcirculating auto-antibodies, by the counts of CD4+ and CD8+ lymphocytes,and by the symptomatology of particular autoimmune disorders, e.g.systemic lupus erythematosis, rheumatoid arthritis, etc.

[0055] “Elevated”, as used in connection with SHBG levels, refers to anSHBG serum concentration measured in a given woman that is greater thanthe mean value for healthy premenopausal women reported by the clinicallaboratory in which the SHBG level is measured. For example, a valueobtained by using the immunoradiometric assay methodology of EndocrineSciences using their immunoradiometric assay would be consideredelevated if it is greater than 84 nmole/Liter. A “substantiallyelevated” SHBG level refers to an SHBG serum concentration in a givenwoman that is greater than the upper limit of the normal range forhealthy premenopausal women reported by the clinical laboratory in whichthe SHBG level is measured. For example, a value obtained by using theimmunoradiometric assay methodology of Endocrine Sciences would beconsidered substantially elevated if it were greater than 185nmole/Liter. In view of the different methods used to measure SHBG indifferent clinical reference laboratories and the correspondingvariations in mean values and normal ranges reported by them, thedefinitions for elevated and substantially elevated SHBG values givenabove are applicable to any validated method with properly determinednormal ranges.

[0056] “Effective amount” refers to an amount of a substance which issufficient to achieve its intended purpose or effect. Various biologicalfactors may affect the ability of a delivered substance to perform itsintended task. Therefore, an “effective amount” may be dependent on suchbiological factors. By way of example without limitation, a woman havingan SHBG serum level of 225 nmole/L may require a greater testosteronedosage to achieve an intended effect, than a woman having an SHBG serumlevel of 100 nmole/L. Therefore, while the testosterone dosages in suchwomen would vary, each dosage would be considered to be an “effectiveamount” as long as it achieves its desired effect. Determination of an“effective amount” is well within the ordinary skill in the art.

[0057] Many evaluations may be employed for measuring the achievement ofdesired effects in the case of androgen and estrogen delivery, which arewell known in the art. Such evaluations may be performed by a physician,or other qualified medical personnel, and may include physicalexamination, blood tests, etc.

[0058] “Therapeutic effect” refers to a desired result which is achievedto some degree. In the context of androgen and estrogen supplementationas presented in the present patent application, a number of desiredresults are referred to as “improving health.” In one aspect,therapeutic effects may be achieved by delivering an “effective amount”of a substance capable of achieving the desired result to a selecteddegree. While the achievement of therapeutic effects may be measured bya physician or other qualified medical personnel using evaluations knownin the art, it is recognized that individual variation and response totreatments may make the achievement of therapeutic effects a subjectivedecision.

[0059] Concentrations, amounts, solubilities, and other numerical datamay be presented herein in a range format. It is to be understood thatsuch range format is used merely for convenience and brevity and shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited.

[0060] For example, a concentration range of 0.5 to 15 pg/ml should beinterpreted to include not only the explicitly recited concentrationlimits of 0.5 pg/ml and 15 pg/ml, but also to include individualconcentrations within that range, such as 0.5 pg/ml, 0.7 pg/ml, 1.0pg/ml, 5.2 pg/ml, 11.6 pg/ml, 14.2 pg/ml, and sub-ranges such as 0.5-2.5pg/ml, 4.8-7.2 pg/ml, 6-14.9 pg/ml, etc. This interpretation shouldapply regardless of the breadth of the range or the characteristic beingdescribed.

[0061] B. The Invention

[0062] Recent research has shown that androgens, and particularlytestosterone, contribute substantially to a woman's health andwell-being. Ebert, et al., U.S. Pat. No. 5,460,820, in one aspect,teaches a composition and method for administering testosteronetransdermally via a patch delivery system. These compositions andmethods maintain total testosterone serum blood levels in a“physiological range” of between about 15 to 80 ng/dL by means oftransdermally administering about 50 to 500 mcg/day of testosterone froma testosterone matrix. It is recognized that non-oral delivery ofandrogens is safer to the liver and provides more sustained deliverythan oral routes since the first pass metabolism effects are bypassed.On the other hand, oral delivery of estrogens allows for an improvedserum lipid profile. However, it has been discovered that theabove-stated total testosterone serum levels for females may not be anaccurate indicator of therapeutically effective testosterone levels inwomen with elevated, or substantially elevated SHBG levels, such asthose women receiving oral estrogens.

[0063] The binding of testosterone to SHBG is known to decrease thetransport of testosterone to androgen sensitive tissues, e.g. tissuesexpressing androgen receptors. Such binding is also known to decreasethe metabolic clearance rate of testosterone in both men and women. See,for example, Vermeulen et al. Metabolic Clearance Rate andInterconversion of Androgens and the Influence of the Free AndrogenFraction, J. Clinical Endocrinology and Metabolism Vol 48:320-326(1979); Longcope et al. Free Estradiol, Free Testosterone, and SexHormone-Binding Globulin in Perimenopausal Women, J. ClinicalEndocrinology and Metabolism Vo. 64:513-518 (1987). As a consequence ofthe influence of SHBG levels on testosterone binding and clearance, theserum levels of total, free, and bioavailable androgen that are attainedby administering androgen to a given individual will be dependent on theSHBG level of that individual. However, the influence of SHBG levels onthe attained serum levels of androgen cannot be precisely predicted fromcurrent knowledge and experimental data are needed.

[0064] To provide such data, pharmacokinetic studies were performed inthree groups of surgically menopausal women who were administered a 300mcg/day testosterone transdermal matrix patch twice-a-week for 7 days.One group had received no estrogen replacement therapy (ERT) for atleast one month, the second group was receiving transdermal estadiol(E2) at a dosage of 0.1 mg/day, and the third group was receiving oralconjugated equine estrogens (CEE) at a dosage of 1.25 mg/day.Measurements of the SHBG level, obtained prior to patch application, andof total and free testosterone levels, obtained before and during thesecond 3.5 day patch application period, were made by EndocrineSciences. The resultant hormone data (mean±SEM) for the three groups ofsurgically menopausal women participating in the clinical study issummarized in Table 2 below.

[0065] It should be noted that the normal range for SHBG levels is 36 to185 nmol/L using the Endocrine Sciences assay. Further, changes in totaltestosterone and free testosterone levels represent the time-averagechanges from change from baseline levels during a 3.5 day patchapplication. TABLE 2 Transdermal E2 Oral CEE (1.25 Hormone No ERT (0.1mg/day mg/day) (unit) n = 19 n = 12 n = 13 SHBG (nmol/L) 85.6 ± 9.6 90.8 ± 12.9 226.3 ± 13.5  Changes in 57.2 ± 4.4  53.6 ± 7.2  70.8 ± 9.6 Total T (ng/dl) Changes in 4.60 ± 0.40 4.20 ± 0.70 2.56 ± 0.30 Free T(pg/mL)

[0066] As shown in Table 2, the mean SHBG level in the oral estrogengroup was approximately 2.5-fold larger than the other groups andexceeded the upper limit of the normal range. SHBG levels in thetransdermal estrogen group were comparable to the women who did notreceive estrogen replacement therapy (ERT). The mean increase in totalserum testosterone levels during patch application, i.e. thetime-averaged change from baseline, was approximately 30% greater in theoral estrogen group in comparison to the other two groups.

[0067] In contrast the mean increase in free serum testosterone level inthe oral estrogen group was approximately 40% lower than in the othertwo groups. These findings indicate that by reducing testosteroneclearance, elevated SHBG levels lead to an increase in the total serumlevels of testosterone obtained during transdermal testosteroneadministration. However, despite the elevation in total serum levels,the free serum testosterone levels, and by inference, the bioavailableserum testosterone levels, are reduced by the elevated SHBG levels,presumably due to the increased binding of testosterone by SHBG. Thesefindings are new and unexpected and could not have been predicted fromearlier studies.

[0068] As a further illustration of the novel effects of SHBG ontestosterone levels, the individual increments of total serumtestosterone and free serum testosterone, obtained during 300 mcg/daytransdermal testosterone administration to surgically menopausal womenreceiving transdermal or oral estrogen, are plotted versus theindividual SHBG levels in FIGS. 1 and 2, respectively. As depicted onlogarithmic scales, the increments in total serum testosterone becomelarger with increasing SHBG levels, whereas the increments in freetestosterone become smaller as the SHBG levels increase.

[0069] To further illustrate the novel and unexpected influence ofelevated SHBG levels on the non-oral administration of testosterone,Table 3 below provides estimates of the testosterone delivery rateneeded to achieve a given increase in free testosterone (FT) were madeas a function of the SHBG level using the power-law regression equationgiven in FIG. 2. As shown in Table 3, the necessary delivery rate toachieve a given increase (change) in FT increases markedly as the SHBGlevel increases. For example, the delivery rate needed to achieve anincrease of 15 pg/mL in a patient whose SHBG level is 700 nmol/Liter isestimated to be 2484 mcg/day, a value substantially greater than taughtin the prior art. TABLE 3 SHBG (nmol/L): 50 84 100 200 400 600 700Change in FT Estimated Delivery Rate (pg/mL) (mcg/day) 1 55 69 74 98 131155 166 2.5 139 172 185 246 328 388 414 5 277 344 369 492 656 777 828 10554 687 739 985 1313 1553 1656 15 831 1031 1108 1477 1969 2330 2484

[0070] For the delivery rates given above, the changes in totaltestosterone level (ng/dL) corresponding to a desired change in freetestosterone level and a given SHBG level can be predicted using thepower-law regression equation shown in FIG. 1. Table 4 below provides anillustration of such predictions. As shown in Table 4, the changes intotal testosterone level corresponding to a given change in freetestosterone level increase markedly as the SHBG level increases. Forexample, the case corresponding to a change in free testosterone of 15pg/mL in a patient whose SHBG level is 700 nmole/Liter (i.e. a deliveryrate of 2484 mcg/day), the predicted increase in total testosterone is820 ng/dL. TABLE 4 SHBG (nmol/L): 50 84 100 200 400 600 700 Change in FTPredicted Changes in Total Testosterone (pg/mL) (ng/dL) 1 9 12 14 23 3749 55 2.5 21 31 35 57 92 123 137 5 43 61 69 113 184 245 273 10 85 123139 226 368 490 547 15 128 184 208 339 553 736 820

[0071] It should be appreciated that in extrapolating the findings andpredictions of Tables 2, 3 and 4 to an actual patient, one must add thepatient's baseline testosterone level (i.e. the level of total or freetestosterone prior to treatment) to the expected change in testosteronelevel from the treatment. For individuals with baseline levels that aresubnormal, the final hormone levels attained by treatment will be closeto the change itself.

[0072] The above findings and predictions indicate that androgenadministration to women on oral estrogens, or who have elevated SHBGlevels in general, would produce free and/or bioavailable testosteronelevels that would be significantly lower compared to women who are onnon-oral estrogen therapy or who have low or normal SHBG levels. Inaddition, women on oral estrogen therapy, or women with elevated SHBGlevels in general, would require androgen doses that may exceed thosepreviously considered optimal in women with normal SHBG levels. Further,the administration of such doses would produce levels of total serumtestosterone above the generally recognized normal ranges. It shouldalso be noted that for some therapeutic applications, e.g. short termapplications of androgens, the desired therapeutic levels of free and/orbioavailable testosterone could also be greater than the correspondingnormal physiological ranges. Accordingly, the present invention providesmethods, compositions, and kits for administering an androgenic steroidto improve the health of a woman, under conditions where the woman'sSHBG levels are elevated.

[0073] C. The Various Aspects

[0074] In one aspect, the invention presents a method and a kit foradministering sex hormones, such as androgens and estrogens to women. Inanother aspect, the present invention presents a method and kit fornon-orally administering androgenic steroids to a woman having elevatedSHBG levels, in order to alleviate symptoms attributable to anandrogenic hormone deficiency. In yet another aspect, the presentinvention provides a method and kit for non-orally administeringandrogenic steroids to a woman who is receiving oral estrogensupplementation. In a further aspect, the present invention provides amethod and kit for coadministering an orally administered estrogen, anda non-orally administered androgenic steroid. These methods and kits foradministering estrogen and/or androgenic steroids have been found usefulin improving health, sexual function, and well-being.

[0075] In one aspect of the present invention, androgen may beadministered at a dose sufficient to achieve a therapeutic effectequivalent to a free testosterone serum level of from about 0.5 to about30 pg/ml. In another aspect of the invention, androgen may beadministered at a dose sufficient to achieve a therapeutic effectequivalent to a free testosterone serum levels of from about 1 to about15 pg/ml. In another aspect of the invention, androgen may beadministered at a dose sufficient to achieve a therapeutic effectequivalent to a free testosterone serum level of from about 1.3 to about6.8 pg/ml, or from about 2 to about 7 pg/ml. In yet another aspect ofthe invention, androgen may be administered at a dose sufficient toachieve a therapeutic effect equivalent to a free testosterone serumlevel of from about 3 to about 10 pg/ml.

[0076] In one aspect of the present invention, an androgen may beadministered at a dosage sufficient to achieve a therapeutic effectequivalent to a bioavailable testosterone serum level of from about 1 toabout 70 ng/dl. In another aspect of the present invention, an androgenmay be administered at a dosage sufficient to achieve a therapeuticeffect equivalent to a bioavailable testosterone serum level of fromabout 2 to about 35 ng/dl. In yet another aspect of the presentinvention, an androgen may be administered at a dosage sufficient toachieve a therapeutic effect equivalent to a bioavailable testosteroneserum level of from about 2 to about 13 ng/dl.

[0077] In one aspect of the present invention, an androgen may beadministered at a dosage sufficient to achieve a therapeutic effectequivalent to a total testosterone serum level of from about 15 to about1000 ng/dl. In another aspect of the invention an androgen may beadministered at a dosage sufficient to achieve a therapeutic effectequivalent to a total testosterone serum level of from about 85 to about1000 ng/dl. In a further aspect of the invention, the androgen may beadministered at a dosage sufficient to achieve a therapeutic effectequivalent to a total testosterone serum level of from about 100 toabout 1000 ng/dl.

[0078] In one aspect of the invention, an androgen may be administeredin a dosage sufficient to achieve a therapeutic effect equivalent toequivalent to a testosterone dosage of at least about 50 mcg/day. Inanother aspect, an androgen may be administered in a dosage sufficientto achieve a therapeutic effect equivalent to a testosterone dosage offrom about 75 to about 3000 mcg/day. In a further aspect, an androgenmay be administered at a dosage sufficient to achieve a therapeuticeffect equivalent to a testosterone dosage of testosterone of from about600 to about 3000 mcg/day. In yet another aspect, an androgen may beadministered at a dosage sufficient to achieve a therapeutic effectequivalent to a testosterone dosage of testosterone of from about 700mcg/day to about 3000 mcg/day.

[0079] One of the non-oral routes of delivery for an androgen dose istopical administration. Topical formulations may include a skinpermeation enhancer(s) to enhance the level of skin flux of theandrogen. Examples, without limitation, of skin permeation enhancersthat may be used are described or referred to in U.S. Pat. Nos.5,122,383 and 5,153,997 the disclosures of which as they relate to skinpermeation enhancers are incorporated by reference. Further, an index ofpermeation enhancers is disclosed by David W. Osborne and Jill J. Henke,in their internet publication entitled Skin Penetration Enhancers Citedin the Technical Literature, which may be found at the worldwide webaddress known as: pharmtech.com/technical/osborne/osborne.htm, which isincorporated by reference herein. An effective amount of an enhancer maybe incorporated into a pharmaceutically acceptable carrier. Variouscarriers will be suitable based on the type of delivery formulationdesired. By way of example without limitation, when an adhesive matrixtransdermal patch is desired, the carrier may be an adhesive. In anotheraspect, when a liquid reservoir system (LRS) patch is desired, thecarrier may be a gel, cream, ointment, lotion, or other suitableformulation known in the art.

[0080] Transdermal patches for transdermal delivery of androgenicsteroids may be manufactured by conventional techniques used in the artof transdermal drug delivery devices. For instance, androgens, carrier,and enhancers may be mixed in desired proportions to form a homogeneousmixture and incorporated into a transdermal device. Various techniquesare known in the art for making various types of transdermal devicessuch as adhesive matrix patches and liquid reservoir system (LRS)patches.

[0081] In addition to transdermal testosterone patches, other non-oralsystems for delivering androgens include but are not limited to:intra-muscular injections of testosterone esters, subcutaneous implantsof fused testosterone, and topical preparations of testosterone,methyltestosterone and other androgens. Devices and methods for thosenon-oral applications are well known in the art.

[0082] The need for supplementing sex hormones such as estrogen andandrogenic steroids should be determined by a physician or other healthcare professional based on monitoring signs and symptoms of sex hormonedeficiency or based on need for pharmacological intervention ofconditions that are responsive to hormonal therapy. Not every femalewill exhibit the same symptoms and it is possible that sex hormonelevels might even be within accepted physiological ranges but, based onother factors, for example, increased SHBG, sex hormone supplementationmay still be appropriate.

[0083] Symptoms of subfunctional levels of androgens, includingtestosterone, might include, but not be limited to: sexual dysfunction,which can manifest in loss of sexual desire, decreased sensitivity tosexual stimulation, decreased arousability and capacity for orgasm;diminished vital energy; depressed mood; diminished sense of well-being;increased shyness; loss of muscle mass and function; unfavorable bodycomposition, i.e., lean to fat mass ratio; thinning and loss of pubichair; urogenital atrophy; dry and brittle scalp hair; dry skin;decreased cognitive abilities; dry eyes; autoimmune phenomena orexacerbation thereof, and a combination thereof.

[0084] Women who are receiving oral estrogens can also benefit fromandrogen therapy as it may reduce the breast tenderness that can occurwith estrogen usage. Owing to known breast tissue anti-proliferativeeffects, androgens may also reduce the excess risk of breast cancerassociated with estrogen use. It is therefore highly desirable, if notimperative, that testosterone supplementation for a female patient bebased on a diagnosis by a physician who prescribes the mode ofapplication, dosage and duration of treatment.

[0085] In so far as it is coadministered with androgenic steroids,estrogen, such as conjugated equine estrogen, may be administered orallyin a dosage range of between about 0.2 to 3.0 mg/day. The dose may beadjusted according to an individual woman's needs and the potency ofestrogen administered. The dose of oral estrogens can be taken in asingle daily dose or in two or more smaller quantities. Ideally, forwomen who are experiencing vasomotor symptoms, the lowest effective doseof estrogen is used to control for vasomotor instability. Lower dosesmay be used in women who do not suffer vasomotor symptoms but willbenefit from other health benefits, such as cardiovascular and bonebenefits. In the case of oral contraceptive use, ethinyl estradiol istypically given cyclically in a 21 day on, 7 day placebo regimen.

[0086] In one aspect the present invention provides a method and kit foradministering a progestin with androgen and estrogen. Progestins areknown for administration to women to protect against endometrialhyperplasia. Progestins are also essential active ingredients of manyoral contraceptive formulations. In accordance with one aspect of thepresent invention, progestins may be administered by any method known inthe art according to individual need. The amount of progestin which iseffective in achieving a desired purpose may vary from woman to woman.Methods for determining an effective amount of progestin, i.e. an amountsufficient to achieve a desired therapeutic effect, are well known tothose ordinarily skilled in the art.

[0087] Based on the above dosages and laboratory tests, one skilled inthe art can readily determine what amount of a particular androgenicsteroid or testosterone derivative to administer to achieve the desiredandrogenic steroid serum levels, which can be achieved using more thanone androgenic steroid, or form of testosterone. What is important isthat the dose of the androgenic steroid or testosterone derivative besufficient to benefit the recipient woman without administering toogreat a dosage. Administering appropriate dosage levels to obtain theoptimal risk/benefit ratio is well within the ordinary skill.

[0088] In the embodiments contained in the following examples, a dosageof about 50-3000 mcg/day of an androgenic steroid is administered to awoman receiving oral estrogen in an estrogen replacement therapy (ERT)regimen or as an oral contraceptive. Doses in this range are usuallysufficient to obtain a therapeutic response. However, the dosage mostappropriate for a particular woman can be determined empirically (e.g.,by varying the delivery dosage and assessing the resulting effects onlibido, sexual function, mood, a general sense of well being, etc.).Therefore, due to the natural variation in hormone sensitivity, theexact dosage is not as critical as is obtaining a resultantphysiological response for a particular patient, which can correspond toa total testosterone serum level of from about 15 to about 400 ng/dl, ora free testosterone serum level of from about 0.5 to about 15 pg/mL.

[0089] The following examples are intended to be merely illustrative ofthe various aspects of the invention disclosed herein and are notintended in any way to limit the scope of the claimed invention. Otheraspects of the invention that are considered equivalent by those skilledin the art are also within the scope of this invention.

EXAMPLE 1

[0090] In surgically menopausal women between the ages of 20 and 55years, oral estrogen and transdermal testosterone were administered asfollows. The estrogen consisted of conjugated equine estrogen (Premarin®tablets) at a daily dose of 0.625 to 2.5 mg. The transdermaltestosterone was administered by a matrix type transdermal patch thatwas applied to the abdomen twice weekly and has a delivery rate of 300mcg/day. The duration of coadministration was 12 weeks. After 12 weeks,this regimen improved sexual function, mood and well-being in comparisonto administration of conjugated equine estrogen alone.

[0091] Serum hormone levels measured on this regimen by EndrocrineSciences (Calabassas Hills, Calif.) were found to be in the followingranges: total testosterone (15.5 to 254.3 ng/dL), free testosterone (1.7to 33.7 pg/mL), bioavailable testosterone (2.3 to 71 ng/dl), estradiol(5 to 280 pg/mL), and estrone (8 to 410 pg/mL). Levels of sex hormonebinding globulin ranged from 62.7 to 563 nmol/L with 92% being elevatedand 48% being substantially elevated according to the definitions of“elevated,” and “substantially elevated,” provided herein. It isnoteworthy that 73% of the women on the regimen of oral estrogen andtransdermal testosterone achieved total testosterone levels in excess of80 ng/dL, the upper limit of the normal range generally recognized inthe art. In contrast, 78% had a free testosterone level below 6.8 pg/mL(the upper limit of the normal range for Endocrine Sciences), and 97%had a free testosterone level below 15 pg/mL, which is within thetherapeutically acceptable range contemplated herein. Similarly, 68% ofthe women had a bioavailable tesosterone level below 12.7 ng/dL (theupper limit of the normal range for Endocrine Sciences), and 97% had abioavailable testosterone level below 35 ng/dL, which is within thetherapeutically acceptable range contemplated herein.

EXAMPLE 2

[0092] A combination of an androgenic compound and an estrogeniccompound may be administered to women who are naturally menopausalaccording the following regimen:

[0093] Androgen: topical administration of testosterone in anappropriate carrier vehicle, such as a cream or ointment, thatoptionally contains a permeation enhancer as needed in order to achievedesired testosterone serum levels. The androgen cream may contain cetylesters, cetyl alcohol, white wax, glyceryl monosterate, propylene glycolmonosterate, methyl stearate, benzyl alcohol, sodium lauryl sulfate,glycerin, and mineral oil. Each gram of the cream contains about 400 mcgtestosterone. About 1 gram of the cream is applied to the skin orabdomen at bedtime. Serum concentrations of free testosterone achievedmay be in the range of 0.5-15 pg/mL, and total testosterone achieved maybe in the range of 30-250 ng/dL.

[0094] In order to control the amount of testosterone administered, ameter dosing device may be employed. Dose adjustments can be made on thebasis of either symptom relief, e.g. restored libido, or to achieve thedesired free testosterone serum concentrations. Ranges for symptomaticrelief may vary between 1-20 pg/mL of free serum testosterone.

[0095] Estrogenic compound: oral conjugated equine estrogens tablets maybe given at a starting dose of 0.625 mg/day. When necessary, doses areadjusted upward to 1.25 mg/day for better control of symptoms, ordownward to 0.3 mg/day as vasomotor symptoms subside to maintain boneand serum lipid benefits.

[0096] In women who have an intact uterus, it is important that asufficient amount of progesterone be present in the serum to avoidendometrial hyperplasia that can result from unopposed estrogenreplacement therapy.

[0097] Benefits of a combined hormone regimen may be perceived by thepatient within the first 6 weeks of administration, but variableresponses may occur. Typically, hormones are administered on a chronicbasis for health maintenance.

EXAMPLE 3

[0098] An androgenic compound and an estrogenic compound may beadministered to women who are post-menopausal to alleviate signs andsymptoms associated with frailty, such as the loss of bone and musclemass and function, reduced cognitive abilities and diminished energy.

[0099] Androgen: intramuscular injection of 150 mg testosteroneenanthate on a monthly basis. Testosterone enanthate may be formulatedto contain 200 mg per mL in sesame oil. In order to provide 150 mg oftestosterone enanthate, the injected dose is 0.75 mL.

[0100] Estrogen: oral estrogens are given in a range of 0.3 to 3.0mg/day.

[0101] Administration is performed as long as benefits of treatment aredesired and deemed appropriate by a prescribing physician.

EXAMPLE 4

[0102] An androgenic compound and an estrogenic compound may beadministered to women with premature ovarian failure, e.g., women whoseovarian function permanently ceases prior to age 40.

[0103] Androgen: methyltestosterone may be delivered via the buccalroute at a dose of 1 mg/day to achieve an improvement in sexual functionthat is equally efficacious to an improvement produced by testosteroneat serum levels of about 50 to 300 ng/dL. The buccal tablet may be abilayer tablet consisting of a drug layer and a bio-adhesive layer (both50 mg each). The composition of the drug layer (in weight percent) maybe 2% methyltestosterone, 0.75% magnesium stearate, 0.1% FD&C yellow #6,24% Klucel HXF, and 73.15% mannitol. The composition of the bio-adhesivelayer (in weight percent) may be 69.25% polyethylene oxide, 30% carbomer934P, and 0.75% magnesium stearate. The adhesive side of the tablet isaffixed to the gingiva of the upper jaw and the drug side of the tabletfaces the overlying buccal mucosa. Drug is absorbed transmucosally asthe tablet dissolves over time. The tablet may be applied once dailyafter breakfast.

[0104] Estrogen: Estrace®, Bristol-Myers Squibb Co., an oral micronizedestradiol product in tablet form, may be administered at a dosage of 2mg/day to alleviate menopausal symptoms and prevent bone loss.

[0105] In addition a progestin, such as medroxyprogesterone acetate, maybe orally administered at a dose of 5 mg/day for the last ten days ofeach month to induce endometrial sloughing.

[0106] While the examples have been directed primarily to the deliveryof an androgenic steroid to provide needed supplementation based ondetermination of a need for such, the administration will be concurrentwith the oral administration of estrogen formulations.

What is claimed is:
 1. A method of improving health in a woman having anelevated or substantially elevated level of sex hormone binding globulin(SHBG) comprising non-orally administering an androgenic steroid in anamount sufficient to provide a therapeutic effect in the presence ofelevated or substantially elevated SHBG levels.
 2. The method of claim1, wherein the woman is receiving oral estrogen supplementation.
 3. Themethod of claim 2, wherein the oral estrogen and the non-oral androgenicsteroid are coadministered.
 4. The method of claim 2, wherein saidandrogenic steroid is a member selected from the group consisting of:testosterone, methyltestosterone, androstenedione, adrenosterone,dehydroepiandrosterone, oxymetholone, fluoxymesterone,methandrostenolone, testolactone, pregnenolone,17α-methylnortestosterone, norethandrolone, dihydrotestosterone,danazol, oxymetholone, androsterone, nandrolone, stanozolol,ethylestrenol, oxandrolone, bolasterone and mesterolone, testosteronepropionate, testosterone cypionate, testosterone phenylacetate,testosterone enanthate, testosterone acetate, testosterone buciclate,testosterone heptanoate, testosterone decanoate, testosterone caprate,testosterone isocaprate, isomers and derivatives thereof, and acombination thereof.
 5. The method of clam 2, wherein said androgenicsteroid is a member selected from the group consisting of: testosterone,dihydrotestosterone, methyltestosterone, isomers and derivativesthereof, and a combination thereof.
 6. The method of claim 2, whereinsaid androgenic steroid is administered in a dosage sufficient toachieve a therapeutic effect equivalent to a total testosterone serumlevel of from about 15 to about 1000 ng/dl.
 7. The method of claim 6,wherein said androgenic steroid dosage is sufficient to achieve atherapeutic effect equivalent to a total testosterone serum level offrom about 85 to about 1000 ng/dl.
 8. The method of claim 6, whereinsaid androgenic steroid dosage is sufficient to achieve a therapeuticeffect equivalent to a total testosterone serum level of from about 100to about 1000 ng/dl.
 9. The method of claim 2, wherein said androgenicsteroid is administered in a dosage sufficient to achieve a therapeuticeffect equivalent to a free testosterone serum level of from about 0.5to about 30 pg/ml.
 10. The method of claim 9, wherein said androgenicsteroid dosage is sufficient to achieve a therapeutic effect equivalentto a free testosterone serum level of from about 1 to about 15 pg/mL.11. The method of claim 9, wherein said androgenic steroid dosage issufficient to achieve a therapeutic effect equivalent to a freetestosterone serum level of from about 3 to about 10 pg/ml.
 12. Themethod of claim 9, wherein said androgenic steroid dosage is sufficientto achieve a therapeutic effect equivalent to a free testosterone serumlevel of about 1 to about 7 pg/ml.
 13. The method of claim 2, whereinsaid androgenic steroid is administered in a dosage sufficient toachieve a therapeutic effect equivalent to a bioavailable testosteroneserum level of from about 1 to about 70 ng/dl.
 14. The method of claim13, wherein said androgenic steroid dosage is sufficient to achieve atherapeutic effect equivalent to a bioavailable testosterone serum levelof from about 2 to about 35 ng/dl.
 15. The method of claim 13, whereinsaid androgenic steroid dosage is sufficient to achieve a therapeuticeffect equivalent to a bioavailable testosterone serum level of fromabout 2 to about 13 ng/dl.
 16. The method of claim 2, wherein saidandrogenic steroid is administered in a dosage sufficient to achieve atherapeutic effect equivalent to a testosterone dosage of at least about50 mcg/day.
 17. The method of claim 16, wherein said androgenic steroidis administered in a dosage sufficient to achieve a therapeutic effectequivalent to a testosterone dosage of from about 75 to about 3000mcg/day.
 18. The method of claim 16, wherein said androgenic steroid isadministered in a dosage sufficient to achieve a therapeutic effectequivalent to a testosterone dosage of from about 500 to about 2500mcg/day.
 19. The method of claim 16, wherein said androgenic steroid isadministered in a dosage sufficient to achieve a therapeutic effectequivalent to a testosterone dosage of from about 550 to about 2000mcg/day.
 20. The method of claim 2, wherein said non-oral administrationis topical administration, or parenteral administration, or acombination thereof.
 21. The method of claim 20, wherein said parenteraladministration is intramuscular injection, or subcutaneous implantation,or a combination thereof.
 22. The method of claim 20, wherein saidtopical administration is transdermal, transmucosal, or sublingual, or acombination thereof.
 23. The method of claim 2, wherein said improvedhealth is manifest by restoration, enhancement, or improvement of acharacteristic selected from the group consisting of: sexual desire,stimulation to sexual organs, ability to achieve orgasm, pleasure insexual activity, frequency of sexual activity, vital energy, sense ofwell-being, mood and sense of emotional well being, shyness, cognitiveabilities, muscle mass and function, body composition, bone mineraldensity, skin and hair condition, pubic hair, urogenital atrophy,vaginal dryness, dry eyes, health in autoimmune conditions, vasomotorinstability, breast tenderness, symptoms of premenstrual syndrome, and acombination thereof.
 24. The method of claim 2, wherein said estrogen isadministered in a dosage sufficient to achieve a therapeutic effectequivalent to a conjugated equine estrogen dosage of from about 0.2 toabout 3.0 mg/day.
 25. The method of claim 2, wherein said orallyadministered estrogen is a member selected from the group consisting of:17β-estradiol, 17α-estradiol, conjugated equine estrogen, esterifiedestrogen, micronized estradiol, sodium estrogen sulfate, ethinylestradiol, estrone, tibolone, selective estrogen receptor modulator(SERM), phytoestrogen, isomers and derivatives thereof, and acombination thereof.
 26. The method of claim 2, wherein said orallyadministered estrogen is a conjugated equine estrogen.
 27. The method ofclaim 2, wherein said orally administered estrogen is an esterifiedestrogen.
 28. The method of claim 2, wherein said orally administeredestrogen is micronized estradiol.
 29. The method of claim 2, furthercomprising administering an effective amount of a progestin sufficientto provide endometrial safety.
 30. The method of claim 2, furthercomprising administering an amount of progestin sufficient to provideeffective contraception.
 31. A kit for improving the health of a womanhaving an elevated, or substantially elevated level of sex hormonebinding globulin (SHBG), comprising a non-oral dosage form of anandrogenic steroid, in an amount sufficient to provide a therapeuticeffect in the presence of elevated, or substantially elevated SHBGlevels.
 32. The kit of claim 31, wherein said androgenic steroid is amember selected from the group consisting of: testosterone,methyltestosterone, androstenedione, adrenosterone,dehydroepiandrosterone, oxymetholone, fluoxymesterone,methandrostenolone, testolactone, pregnenolone,17α-methylnortestosterone, norethandrolone, dihydrotestosterone,danazol, oxymetholone, androsterone, nandrolone, stanozolol,ethylestrenol, oxandrolone, bolasterone and mesterolone, testosteronepropionate, testosterone cypionate, testosterone phenylacetate,testosterone enanthate, testosterone acetate, testosterone buciclate,testosterone heptanoate, testosterone decanoate, testosterone caprate,testosterone isocaprate, isomers and derivatives thereof, and acombination thereof.
 33. The kit of claim 31, wherein said androgenicsteroid is present in a non-oral dosage form sufficient to achieve atherapeutic effect equivalent to a total testosterone serum level offrom about 15 to about 1000 ng/dl.
 34. The kit of claim 31, wherein saidandrogenic steroid is present in a non-oral dosage form sufficient toachieve a therapeutic effect equivalent to a free testosterone serumlevel of from about 0.5 to about 30 pg/ml.
 35. The kit of claim 31,wherein said androgenic steroid is present in a non-oral dosage formsufficient to achieve a therapeutic effect equivalent to a bioavailabletestosterone serum level of from about 1 to about 70 ng/dl.
 36. The kitof claim 31, wherein said androgenic steroid is present in a non-oraldosage form sufficient to achieve a therapeutic effect equivalent to atestosterone dosage of at least about 50 mcg/day.
 37. The kit of claim31, wherein said non-oral dosage form is a topical or parenteral dosageform, or a combination thereof.
 38. The kit of claim 31, furthercomprising an effective amount of an estrogen in an oral dosage form.39. The kit of claim 38, wherein said estrogen is present in a dosageform sufficient to achieve a therapeutic effect equivalent to aconjugated equine estrogen dosage of from about 0.2 to about 3.0 mg/day.40. The kit of claim 38, wherein said estrogen is a member selected fromthe group consisting of: 17α-estradiol, 17β-estradiol, conjugated equineestrogen, esterified estrogen, micronized estradiol, sodium estrogensulfate, ethinyl estradiol, estrone, selective estrogen receptormodulator (SERM), phytoestrogen, isomers and derivatives thereof, and acombination thereof.
 41. The kit of claim 38, further comprising aneffective amount of a progestin sufficient to provide endometrialsafety.
 42. The kit of claim 38, further comprising an effective amountof a progestin sufficient to provide effective contraception.